During the last five years of NIH funding, we have made significant progress in accomplishing the specific aims outlined in the original research project. The findings summarized in the Progress Report indicate three major lines of interactions between the spinal cord N-methyl-D-aspartate (NMDA) and opioid receptor systems in relation to hyperalgesia and opioid tolerance. Moreover, these findings reveal potentially irreversible degenerative neuronal changes associated with hyperalgesia and opioid tolerance. Since NMDA and opioid receptors represent two important systems in nociception-related neuroplasticity and antinociception, the goal of this competing grant renewal is to continue the fruitful work carried out over the last funding period and to further investigate neural and molecular mechanisms of interactions between these two receptor systems. Multidisciplinary approaches including behavioral, pharmacological, and immunocytochemical methods will be used to accomplish three specific aims: (1) To examine co-localization of NMDA and p-opioid receptors in spinal cord neurons and to determine the topographic distribution of such co-localization in rats with and without hyperalgesia or mu-opioid tolerance; (2) To examine the nature of degenerative neuronal changes in the spinal cord associated with hyperalgesia and p-opioid tolerance and to explore the time course and dose-response relationship of opioid treatment with the occurrence of degenerative neuronal changes; and (3) To determine the role of NMDA receptor activation and related intracellular changes in degenerative neuronal changes associated with p-opioid tolerance. This proposed work is a logical continuation of previous studies, which will provide novel and important information on cellular and intracellular interactions between NMDA and p-opioid receptors and on the role of such interactions in hyperalgesia and p-opioid tolerance. Thus, the results from this work may help improve the clinical utility of opioid analgesics in treating cancer and chronic pain syndromes. Importantly, investigations of opioid-induced degenerative neuronal changes and their relation to pathophysiological pain states may provide insights into the neurobiology of both hyperalgesia and opioid tolerance, which could result in additional clinical applications.